Agouti Signaling Protein Inhibits Melanogenesis and the Response of Human Melanocytes to α-Melanotropin

Abstract

In mouse follicular melanocytes, the switch between eumelanin and pheomelanin synthesis is regulated by the extension locus, which encodes the melanocortin-1 receptor (MC1R) and the agouti locus, which encodes a novel paracrine-signaling molecule that inhibits binding of melanocortins to the MC1R. Human melanocytes express the MC1R and respond to melanotropins with increased proliferation and eumelanogenesis, but a potential role for the human homolog of agouti-signaling protein, ASIP, in human pigmentation has not been investigated. Here we report that ASIP blocked the binding of alpha-melanocyte-stimulating hormone (alpha-MSH) to the MC1R and inhibited the effects of alpha-MSH on human melanocytes. Treatment of human melanocytes with 1 nM-10 nM recombinant mouse or human ASIP blocked the stimulatory effects of alpha-MSH on cAMP accumulation, tyrosinase activity, and cell proliferation. In the absence of exogenous alpha-MSH, ASIP inhibited basal levels of tyrosinase activity and cell proliferation and reduced the level of immunoreactive tyrosinase-related protein-1 (TRP-1) without significantly altering the level of immunoreactive tyrosinase. In addition, ASIP blocked the stimulatory effects of forskolin or dibutyryl cAMP, agents that act downstream from the MC1R, on tyrosinase activity and cell proliferation. These results demonstrate that the functional relationship between the agouti and MC1R gene products is similar in mice and humans and suggest a potential physiologic role for ASIP in regulation of human pigmentation.

SOX9 is a key player in ultraviolet B-induced melanocyte differentiation and pigmentation

“…ASP is an antagonist of the melanocortin 1 receptor, which plays a key role in regulating pigmentation (21). ASP inhibits melanin formation in mouse melanocytes and in melanoma cells as well as in NHM (22)(23)(24). We treated NHM obtained from neonatal moderately pigmented (n-MP) skin with ASP.…”

Segmented heterochromia in scalp hair

“…Agouti signaling protein antagonizes the action of ␣-melanocyte-stimulating hormone and inhibits eumelanin synthesis and tyrosinase activity. 7 It may be applicable to humans because the messenger RNA for agouti signaling protein is expressed in various human tissues. 8 Although we failed to detect the messenger RNA for agouti signaling protein from the biopsy specimens by polymerase chain reaction (data not shown), it may be possible that melanocytes in the hair bulb of this patient produced pheomelanin and eumelanin alternatively, resulting in alternative segmentation of hair shafts.…”

Seeing the gene therapy: application of gene gun technique to transfect and decolour pigmented rat skin with human agouti signalling protein cDNA

“…16 Most studies have proposed that ASP acts by antagonizing the action of a-MSH at MC1R, resulting in decreased cell tyrosinase concentrations leading to suppression of eumelaninogenesis. 6,9 In this study, depigmentation in the rats started as early as day 3 after the pCMV-hASP gene was delivered to their skin using the gene gun ( Figure 1). The effect was most prominent on day 14, but gradually returned to original pigmentation by day 28.…”

“…In vitro studies have shown that human ASP acts in a similar fashion to mouse agouti protein, in that it downregulates melanogenic genes controlling eumelanin synthesis in human melanocytes, and its in vivo expression in transgenic mice gives rise to yellow coat colours. [7][8][9][10] Thus, it appears that the ASP plays an important role in the regulation of mice and human skin pigmentation and hair colour.…”